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Golding, Liam

University of British Columbia

Background: SARS-CoV-2 mRNA vaccines have been shown to generate strong antibody responses against the ancestral Spike protein. When writing this, whether cross variant avidity maturation occurs and to what extent remained was poorly characterized. This thesis describes a highly sensitive, multidimensional assay to measure SARS-CoV-2 anti-Spike and RBD IgG avidity. Effects of extending vaccine intervals on avidity maturation, whether mRNA vaccines induce cross-variant RBD avidity, and potential functional roles of avidity were addressed. Methods: Sera were collected from a healthcare workers cohort. Paired samples were selected at baseline (pre-vaccine), 4-and 12-weeks post-prime, 4 and 24 weeks post-second, and 4 weeks post-third mRNA vaccine doses. Inclusion criteria were adults (≥ 18). I modified a chaotrope-based fractional avidity assay to determine the relative/absolute fractional WU-1 Spike and variant RBD (including WU-1) IgG avidity. Additional outcome measures were competitive anti-RBD ACE-2 blocking antibodies, ADCP, and ADCC. Results: I recruited 353 healthcare workers that provided at least one blood sample between January 2021 and January 2022. For the longitudinal analysis, I selected 8-13 participants who had multiple collections across time points. Spike antibody avidity matured up to 12 weeks post-prime dose, as reflected in an increase in medium, high and very high avidity signals. Longer prime-second dose intervals enhanced antibody avidity towards medium-very RBD avidity profiles. Boosters dose-dependently increased cross-variant anti-RBD IgG maturation in absence of infection. I also show several functional relationships between Spike/RBD IgG antibody levels, antibody avidity profiles, inhibition of ACE-2 binding to Spike or RBD, and other functional antibody properties like Antibody-Dependent Cellular Phagocytosis (ADCP) and Antibody-Dependent Cellular Cytotoxicity (ADCC). iv Conclusions: mRNA vaccines dose-dependently accelerated maturation functional antibody responses to ancestral as well as variant RBD and Spike, including Omicron. Extending the interval between vaccine doses further enhances these antibody responses. These findings highlight the importance of avidity and antibody effector functions in evaluating the effect of booster doses, extended dosing interval and time on that quality of the antibody response.

Text

2023-02-08

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83813

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/